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DE1221490T1 - RECOMBINANT, ADENOVIRAL VECTORS, AND ITS USE IN THE TREATMENT OF DIFFERENT TYPES OF LIVER, KIDNEY AND LUNG FIBROSIS AND HYPERTROPHIC STAINING - Google Patents

RECOMBINANT, ADENOVIRAL VECTORS, AND ITS USE IN THE TREATMENT OF DIFFERENT TYPES OF LIVER, KIDNEY AND LUNG FIBROSIS AND HYPERTROPHIC STAINING

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Publication number
DE1221490T1
DE1221490T1 DE1221490T DE00961245T DE1221490T1 DE 1221490 T1 DE1221490 T1 DE 1221490T1 DE 1221490 T DE1221490 T DE 1221490T DE 00961245 T DE00961245 T DE 00961245T DE 1221490 T1 DE1221490 T1 DE 1221490T1
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mmp
adenoviral vector
recombinant adenoviral
gene
fibrosis
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DE1221490T
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German (de)
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Cordova Estuardo Aguilar
Borunda Juan Armendariz
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TGT Laboratories SA de CV
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TGT Laboratories SA de CV
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Priority claimed from MXPA/A/1999/008515A external-priority patent/MXPA99008515A/en
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Publication of DE1221490T1 publication Critical patent/DE1221490T1/en
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    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C12N9/6491—Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
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Claims (21)

Anmeldungs-Nr. OO 961 245.8 SMB Veröffentlichungs-Nr. 1221490 PatentansprücheApplication No. OO 961 245.8 SMB Publication No. 1221490 Patent claims 1. Rekombinanter adenoviraler Vektor, der ein adenovirales Genom enthält, von dem die offenen Leseraster El und/oder E3 deletiert wurden, das aber noch genügend Sequenz behält, um den adenoviralen Vektor zur Replikation in vitro zu befähigen, wobei der Vektor auch ein therapeutisches Gen oder eine interessierende DNA-Sequenz enthält, das bzw. die von ubiquitären Promotoren und/oder gewebespezifischen Promotoren reguliert wird und therapeutische Proteine codiert, die für die Fibrosebehandlung von Fibröse geeignet sind.1. A recombinant adenoviral vector containing an adenoviral genome from which the El and/or E3 open reading frames have been deleted, but which still retains sufficient sequence to enable the adenoviral vector to replicate in vitro, the vector also containing a therapeutic gene or DNA sequence of interest regulated by ubiquitous promoters and/or tissue-specific promoters and encoding therapeutic proteins suitable for the treatment of fibrosis. 2. Rekombinanter adenoviraler Vektor gemäß Anspruch 1, wobei es sich bei dem gewebespezifischen Promotor um PEPCK handelt.2. Recombinant adenoviral vector according to claim 1, wherein the tissue-specific promoter is PEPCK. 3. Rekombinanter adenoviraler Vektor gemäß Anspruch 1, wobei das in den adenoviralen Vektor einklonierte therapeutische Gen bzw. die DNA-Sequenz ausgewählt ist aus latentem und aktivem humanem Metalloprotease-Gen MMP-8, MMP-I, MMP-2, MMP-9 und MMP-13, humanem Urokinase-Plasminogen-Aktivator-Gen (uPA, Wildtyp und/oder modifiziert), Gen des verkürzten Rezeptors für TGF-ß Typ II und Smad 7, die für therapeutische Proteine codieren, die den Überschuss von collagenischen Proteinen abbauen, die in den zirrhotischen Organen abgeschieden werden.3. Recombinant adenoviral vector according to claim 1, wherein the therapeutic gene or DNA sequence cloned into the adenoviral vector is selected from latent and active human metalloprotease gene MMP-8, MMP-I, MMP-2, MMP-9 and MMP-13, human urokinase plasminogen activator gene (uPA, wild type and/or modified), gene of the truncated receptor for TGF-ß type II and Smad 7, which encode therapeutic proteins that degrade the excess of collagen proteins that are secreted in the cirrhotic organs. 4. Rekombinanter adenoviraler Vektor gemäß Anspruch 3, wobei das therapeutische Gen eine DNA-Sequenz ist, die aus dem Gen des Hepatocytenwachstumsfaktors (HGF) ausgewählt ist, das für Proteine codiert, die die4. Recombinant adenoviral vector according to claim 3, wherein the therapeutic gene is a DNA sequence selected from the hepatocyte growth factor (HGF) gene encoding proteins that hepatische Regeneration stimulieren, um die normalen Funktionen der Leber wiederzuerlangen.stimulate hepatic regeneration to restore normal liver functions. 5. Rekombinanter adenoviraler Vektor gemäß Anspruch 1, wobei es sich bei den therapeutischen Proteinen für die Behandlung von Fibröse um das latente und/oder aktive Protein MMP-8, MMP-I, MMP-2, MMP-9 und MMP-13, Wildtyp- und/oder modifiziertes uPA, den verkürzten Rezeptor für TGF-ßTyp II, Betaglycan, HGF und Smad 7 handelt.5. Recombinant adenoviral vector according to claim 1, wherein the therapeutic proteins for the treatment of fibrosis are the latent and/or active protein MMP-8, MMP-I, MMP-2, MMP-9 and MMP-13, wild-type and/or modified uPA, the truncated receptor for TGF-ß type II, betaglycan, HGF and Smad 7. 6. Rekombinanter adenoviraler Vektor gemäß Anspruch 1, der auch die . Abgabe therapeutischer Gene oder DNA-Sequenzen enthält, die therapeutische Proteine codieren, die für die Behandlung der Fibröse in einer zirrhotischen Leber bestimmt sind.6. Recombinant adenoviral vector according to claim 1, which also contains the delivery of therapeutic genes or DNA sequences encoding therapeutic proteins intended for the treatment of fibrosis in a cirrhotic liver. 7. Rekombinanter adenoviraler Vektor gemäß Anspruch 6, wobei die Abgabe der therapeutischen Gene in anderen Organen mit generalisierter Fibröse durchgeführt wird.7. Recombinant adenoviral vector according to claim 6, wherein the delivery of the therapeutic genes is carried out in other organs with generalized fibrosis. 8. Rekombinanter adenoviraler Vektor gemäß Anspruch 7, wobei die gewebespezifische Erkennung der therapeutischen Gene zu den Organen mit Fibröse durch den verwendeten Verabreichungsweg erfolgt.8. Recombinant adenoviral vector according to claim 7, wherein the tissue-specific detection of the therapeutic genes to the organs with fibrosis occurs through the route of administration used. 9. Rekombinanter adenoviraler Vektor gemäß Anspruch 8, wobei der Verabreichungsweg intravenös ist.9. The recombinant adenoviral vector of claim 8, wherein the route of administration is intravenous. 10. Rekombinanter adenoviraler Vektor gemäß Anspruch 6, wobei die Organe mit Fibröse aus Leber, Lunge, Herz, Niere, Haut und hypertrophen Narben ausgewählt sind.10. Recombinant adenoviral vector according to claim 6, wherein the organs with fibrosis are selected from liver, lung, heart, kidney, skin and hypertrophic scars. 11. Rekombinanter adenoviraler Vektor gemäß Anspruch 10, wobei das Hauptzielorgan die Leber ist.11. Recombinant adenoviral vector according to claim 10, wherein the main target organ is the liver. 2U-11:::-jX::d &egr; /&egr; &rgr; &igr; 2214.90 &tgr;&igr;2U-11:::- j X::d &egr;/&egr;&rgr;&igr; 2214.90 &tgr;&igr; 12. Rekombinante adenovirale Vektoren gemäß den Ansprüchen 1 bis 11, wobei die Abgabe von therapeutischen Genen durch die Verwendung von viralen oder nichtviralen Vektoren erfolgt.12. Recombinant adenoviral vectors according to claims 1 to 11, wherein the delivery of therapeutic genes occurs through the use of viral or non-viral vectors. 13. Rekombinanter adenoviraler Vektor gemäß Anspruch 12, wobei die nichtviralen Vektoren aus Plasmiden sowie kationischen und anionischen Liposomen ausgewählt sind. . ·13. Recombinant adenoviral vector according to claim 12, wherein the non-viral vectors are selected from plasmids and cationic and anionic liposomes. . · 14. Rekombinanter adenoviraler Vektor gemäß Anspruch 6, wobei die effiziente Entsendung des Collagenase-Gens MMP-8 in die zirrhotische Leber mittels Überexpression von Metalloproteasen den Abbau von Collagen induzieren kann.14. The recombinant adenoviral vector of claim 6, wherein efficient delivery of the collagenase gene MMP-8 into the cirrhotic liver via overexpression of metalloproteases can induce collagen degradation. 15. Rekombinanter adenoviraler Vektor gemäß Anspruch 1, dadurch gekennzeichnet, dass er für die Behandlung von hepatischer, pulmonaler, renaler und Herzfibrose, Keloiden und hypertrophen Narben verwendet wird und keine letale Toxizität induziert.15. Recombinant adenoviral vector according to claim 1, characterized in that it is used for the treatment of hepatic, pulmonary, renal and cardiac fibrosis, keloids and hypertrophic scars and does not induce lethal toxicity. 16. ■ Verfahren zur Herstellung von rekombinanten adenoviralen Vektoren16. ■ Method for producing recombinant adenoviral vectors durch die Klonierung der Reporter-Gene LacZ und GFP und des therapeutischen Gens, das therapeutische Proteine für die Behandlung von hepatischer, pulmonaler, renaler und/oder Herzfibrose, Keloiden und hypertrophen Narben codiert. by cloning the reporter genes LacZ and GFP and the therapeutic gene encoding therapeutic proteins for the treatment of hepatic, pulmonary, renal and/or cardiac fibrosis, keloids and hypertrophic scars. 17. Verfahren gemäß Anspruch 16, wobei das therapeutische Gen aus dem latenten und aktiven humanen Metalloprotease-Gen MMP-8, MMP-I, MMP- I1 MMP-9 und MMP-13, dem Wildtyp- und/oder modifizierten Gen für humanes uPA, Smad 7 und dem Gen des verkürzten Rezeptors für TGF-ß Typ II ausgewählt ist.17. The method according to claim 16, wherein the therapeutic gene is selected from the latent and active human metalloprotease gene MMP-8, MMP-I, MMP- I 1 MMP-9 and MMP-13, the wild type and/or modified gene for human uPA, Smad 7 and the gene of the truncated receptor for TGF-ß type II. 18.. Verfahren gemäß Anspruch 16, wobei es sich bei dem rekombinanten adenoviralen Vektor um pAdGFP-MMP-8 handelt.18.. The method of claim 16, wherein the recombinant adenoviral vector is pAdGFP-MMP-8. -4--4- 19. Pharmazeutische Zusammensetzung, die eine therapeutisch wirksame Menge mit einem Behandlungsschema mit Einheitsdosen von Viruspartikeln von rekombinanten adenoviralen Vektoren gemäß Anspruch 1 enthält, für die Behandlung von hepatischer, pulmonaler, renaler und Herzfibrose, Keloiden und hypertrophen Narben, kombiniert mit einem pharmazeutisch annehmbaren Träger.19. A pharmaceutical composition containing a therapeutically effective amount of a unit dose regimen of recombinant adenoviral vector virus particles according to claim 1 for the treatment of hepatic, pulmonary, renal and cardiac fibrosis, keloids and hypertrophic scars combined with a pharmaceutically acceptable carrier. 20. Pharmazeutische Zusammensetzung gemäß Anspruch 19, wobei die Einheitsdosis etwa 107 bis 1014 Viruspartikel für ein Individuum mit Fibröse beträgt.20. The pharmaceutical composition of claim 19, wherein the unit dose is about 10 7 to 10 14 virus particles for an individual with fibrosis. 21. Verwendung des rekombinanten adenoviralen Vektors gemäß Anspruch 1 zur Erarbeitung einer Biomedikation für die Behandlung von hepatischer, pulmonaler, renaler und Herzfibrose, Keloiden und hypertrophen Narben.21. Use of the recombinant adenoviral vector according to claim 1 for the development of a biomedication for the treatment of hepatic, pulmonary, renal and cardiac fibrosis, keloids and hypertrophic scars.
DE1221490T 1999-09-17 2000-09-14 RECOMBINANT, ADENOVIRAL VECTORS, AND ITS USE IN THE TREATMENT OF DIFFERENT TYPES OF LIVER, KIDNEY AND LUNG FIBROSIS AND HYPERTROPHIC STAINING Pending DE1221490T1 (en)

Applications Claiming Priority (2)

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MXPA/A/1999/008515A MXPA99008515A (en) 1999-09-17 Recombinant adenoviral vectors and their utility in the treatment of various types of hepatic, renal, pulmonary fibrosis and hypertrophic scars
PCT/MX2000/000035 WO2001021761A2 (en) 1999-09-17 2000-09-14 Recombinant adenoviral vectors and their utility in the treatment of various types of fibrosis: hepatic, renal, pulmonary, as well as hypertrophic scars

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DE1221490T Pending DE1221490T1 (en) 1999-09-17 2000-09-14 RECOMBINANT, ADENOVIRAL VECTORS, AND ITS USE IN THE TREATMENT OF DIFFERENT TYPES OF LIVER, KIDNEY AND LUNG FIBROSIS AND HYPERTROPHIC STAINING
DE60017924T Expired - Lifetime DE60017924T2 (en) 1999-09-17 2000-09-14 RECOMBINANT, ADENOVIRAL VECTORS AND THEIR USE FOR THE TREATMENT OF LIVER CROP

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US (3) US20030003077A1 (en)
EP (1) EP1221490B1 (en)
JP (1) JP4173663B2 (en)
AR (1) AR025692A1 (en)
AU (1) AU7322600A (en)
CA (1) CA2385538C (en)
CO (1) CO5420199A1 (en)
DE (2) DE1221490T1 (en)
ES (1) ES2183752T3 (en)
HK (1) HK1049860B (en)
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